title: ΔFosB induction correlates inversely with CB₁ receptor desensitization in a brain region-dependent manner following repeated Δ⁹-THC administration.
abstract: Repeated Δ(9)-tetrahydrocannabinol (THC) administration produces desensitization and downregulation of cannabinoid type 1 receptors (CB₁Rs) in the brain, but the magnitude of these adaptations varies among regions. CB₁Rs in the striatum and its output regions exhibit the least magnitude and slowest development of desensitization and downregulation. The molecular mechanisms that confer these region-dependent differences are not known. The stable transcription factor, ΔFosB, is induced in the striatum following repeated THC administration and could regulate CB₁Rs. To directly compare the regional profile of ΔFosB induction and CB₁R desensitization and downregulation, mice were treated with THC (10 mg/kg) or vehicle for 13.5 days. CP55,940-stimulated [(35)S]GTPγS autoradiography and immunohistochemistry were performed to measure CB₁R desensitization and downregulation, respectively, and ΔFosB expression was measured by immunoblot. Significant CB₁R desensitization and downregulation occurred in the prefrontal cortex, lateral amygdala and hippocampus; desensitization was found in the basomedial amygdala and no changes were seen in remaining regions. ΔFosB was induced in the prefrontal cortex, caudate-putamen, nucleus accumbens and lateral amygdala. An inverse regional relationship between ΔFosB expression and CB₁R desensitization was found, such that regions with the greatest ΔFosB induction did not exhibit CB₁R desensitization and areas without ΔFosB induction had the greatest desensitization, with remaining regions exhibiting intermediate levels of both. Dual immunohistochemistry in the striatum showed both CB₁R co-localization with ΔFosB in cells and CB₁R puncta surrounding ΔFosB-positive cells. THC-induced expression of ΔFosB was absent in the striatum of CB₁R knockout mice. These data suggest that transcriptional targets of ΔFosB might inhibit CB₁R desensitization and/or that ΔFosB induction could be limited by CB₁R desensitization.
authors.affiliation: Department of Pharmacology and Toxicology, Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Lazenka
authors.affiliation: Department of Pharmacology and Toxicology, Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
authors.affiliation: Department of Pharmacology and Toxicology, Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA. Electronic address: ljsimsel@vcu.edu.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Sim-Selley
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D013759:Dronabinol / Q000008:administration & dosage*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C483819:Fosb protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D043884:Receptor, Cannabinoid, CB1; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013759:Dronabinol
keywords: Cannabinoid; Caudate-putamen; G-protein; Hippocampus; Nucleus accumbens